Met, also referred to as hepatocyte growth factor receptor (HGFR), is expressed predominantly in epithelial cells but has also been identified in endothelial cells, myoblasts, hematopoietic cells and motor neurons. Overexpression of hepatocyte growth factor and activation of Met has been associated with the onset and progression in a number of different tumor types as well as in the promotion of metastatic disease.
U.S. Published Patent Application US 2005/0245530 A1 discloses monocyclic heterocycle compounds that inhibit the protein tyrosine kinase activity of growth factor receptors such as Met, thus making them useful as anti-cancer agents. As may be appreciated, there remains a need for anti-cancer compounds that are useful for treating Met activated cancer and advantageously have activity against other cancer pathways.
Applicants have found a potent compound that has activity against cancers dependent upon Met activation and also has activity against cancers as a VEGFR inhibitor. Applicants have also discovered prodrugs of the compound useful for administration of the compound in a more soluble form. It is now possible to provide compounds with different pharmacological profiles as compared with currently-known anti-cancer compounds for treating Met activated cancers, and that have stability, bioavailability, solubility, therapeutic index and toxicity values that ensure drugability.